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Herpes vegetans, an atypical herpes lesion in HIV patient:

A case report

Sondang P. Sirait, Wresti Indriatmi Dermatovenereology Department, Faculty of Medicine, Universitas;

Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia

Abstract

Herpes vegetans is a rare form of Herpes simplex virus (HSV) infection in immunocompromised patients that clinically presents as a verrucous and hypertrophic lesion. In this case, we present a 36-year-old man with exophytic verrucous masses in the genital area that was initially suspected as a malignancy. Difficulty to properly diagnose the patient resulted in a few failed attempts at treating the lesion. After excluding other differential diagnoses, the atypical lesion proved to be caused by vegetative herpes infection due to a good response to HSV therapy. Reevaluation of biopsy also showed signs of HSV etiology. Atypical presentation of herpes simplex in immunocompromised patients still proves to be a challenge to diagnose and treat. Proper clinical identification and workup are needed to diagnose and to choose proper regiments.

Introduction

Herpes simplex virus (HSV) infection is a common infection worldwide, it is caused by 2 types of viruses. HSV Type 1 (HSV-1) infections manifest as mucocutaneous infections, mostly associated with orofacial disease. Meanwhile, HSV Type 2 (HSV-2) is usually associated with genital infections.

HSV-2 infections are closely related to extensive genital lesions in different stages of evolution, including vesicles, pustules, and erythematous ulcers that require 2 to 3 weeks to resolve.¹The global prevalence of HSV-2 infections among persons aged 14- 49 years old is 11.9%, which increased especially among patients with co-HIV infection.^2,3

All manifestations of HSV in an immunocompetent host can be seen in an immunocompromised host, but they are more severe, more extensive, more difficult to treat, and highly recurrent. One uncommon form of chronic HSV infection, verrucous HSV or herpes vegetans, occurs both in patients with advanced AIDS and well-

controlled HIV.¹In this variant, the presentation of genital herpes is atypical, which includes chronic ulcerations, papular erup- tions, verrucous lesions which are hyperker- atotic, and eroded vegetating plaques that can continue for long periods.^1,4In this report, we present a case of atypical herpes lesions in HIV that initially mimics malignancy.

Case Report

A 36-year-old man presented with multiple nodules and ulcers on his glans and shaft penis, and pubic area for 4 months prior. He was referred from other dermatol- ogist with squamous cell carcinoma based on fine needle aspiration biopsy (FNAB).

The nodules began to spread and formed ulcerations. A thin white layer on top of the wound was developed. The patient was diagnosed with HIV 6 months before the examination and started antiretroviral (ARV) therapy around that period. He had been diagnosed with genital herpes before.

The patient also had been taking Itraconazole for one week to treat his tinea corporis. There was a positive history of malignancy in his family, a distant relative of his had bladder cancer. On clinical examination, there were multiple erythematous plaques, nodules, and exophytic verrucous masses which were superficially eroded and covered with slough (Figure 1a). These lesions were found on the penile glans, shaft, and pubic area. The rest of the dermatological and systemic examination was normal. We suspected squamous cell carcinoma with differential diagnosis of condyloma lata, bowenoid papulosis, extramam- mary Paget’s, and condyloma acuminata.

A 5 mm punch biopsy was performed, which revealed acanthotic epidermis, spon- giosis, exocytosis of neutrophils and lymphocytes, and basal layer vacuolization.

There were perivascular inflammatory infil- trates composed of lymphocytes, neutrophils, eosinophils, and plasma cells in the superficial and deep dermal layer. Although the histopathological presence of dense inflammatory cells and numerous plasma cells leans toward syphilis, the serologic tests (VDRL and TPHA) showed negative results. Further workup of HPV-genotyping showed positive HPV-DNA but none of the 33 subtypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 81, 82, 6, 11, 26, 40, 42, 43, 44, 54, 55, 57, 61, 70, 71, 72, and 84). Based on these findings, we still cannot rule out the possibility of malignancy. One month later, the lesions were

exudative and painful. With further discussion, the diagnosis was established as atypical condiloma lata on HIV undergoing ARV therapy. The patient was given two doses of 2,4 million units benzathine peni- cillin injection with a week interval in between. A wet NaCl 0,9% compress was also recommended. After one week, the verrucous lesion slightly improved but was still wet and itchy.

Four months later, the patient presented again with complaints of new lesions of plaque, nodules, vesicles, and erosion covered with slough and pus at the penile shaft and glans (Figure 1b,c). In the last four months, the patient had sought a second opinion and was given podophyllin tincture and valacyclovir. The lesions dried and were excised. We reviewed the previous biopsy. The tissue showed ulceration, spon- giosis, multinucleated giant cells with peripheral rimming, perivascular inflamma-

Dermatology Reports 2022; volume 14:9180

Correspondence: Sondang P. Sirait, Faculty of Medicine Universitas Indonesia, Salemba Raya 6, Jakarta, Indonesia.

Tel.: +62816803878

E-mail: [email protected]

Key words:Herpes Vegetans, Atypical Lesion, HIV, HPV.

Contributions: WI was responsible for per- forming clinical examination and taking care of the patient. SPS performed biopsy, read the pathology slides, and taking care of the patient. All authors read and approved the final manuscript.

Conflict of interest: The authors declare no potential conflict of interest.

Funding: None.

Availability of data and material: Data and materials are available by the authors.

Ethical approval and informed consent: Not applicable.

Please cite this article as: Sirait SP, Indriatmi W. Herpes vegetans, an atypical herpes lesion in HIV patient: A case report. Dermatol Rep 2022;14:9180.

Received for publication: 11 April 2021.

Accepted for publication: 21 May 2021.

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).

©Copyright: the Author(s), 2022 Licensee PAGEPress, Italy Dermatology Reports 2022; 14:9180 doi:10.4081/dr.2022.9180

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nb-UVB phototherapy was associated. In May 2019, the psoriasis had further worsened with a PASI of 13. We therefore decid- ed to start a therapy with DMF, recently available in Italy, at increasing dosage as per drug data sheet.

To date, the patient is taking DMF 600mg/day, with good tolerability and complete clinical resolution of psoriasis.

Discussion

Chronic plaque psoriasis is the most common form of psoriasis, affecting about 90% of patients. Nowadays, as a consequence of a better understanding of the pathogenetic mechanisms of the disease, many therapeutic options have become available². Nevertheless, finding the right therapy, especially in complex patients, can still be a challenging task. In moderate to severe psoriasis, the use of systemic therapy is recommended.

In some European countries, fumaric acid esters (FAEs) such as Fumaderm^®, a combination of DMF and monoethyl fumarate salts, have been used for years as a systemic therapy for psoriasis.³ In this combination, DMF is believed to be the primary active ingredient and responsible for efficacy in the treatment of psoriasis.

Therefore in 2017, the European Medicines Agency (EMA) approved Skilarence®, a new oral formulation of DMF for the treatment of adults with moderate-to-severe chronic plaque psoriasis in need of systemic medical therapy.² The safety profile and efficacy of DMF were investigated by the BRIDGE trial,⁴ whereas other previous studies had already investigated the efficacy of FAEs in the treatment of psoriasis.³

In our patient’s case, the existence of important comorbidities limiting the therapeutic range and the failure of multiple ther-

apies have made the management of his psoriasis particularly complex.

Moreover, the treatment of psoriasis in patients with cancer history is especially difficult: malignancy represents at least a relative contraindication to the use of immunosuppressive drugs such as methotrexate or cyclosporine, while the use of biologics is generally considered with caution in patients that have been cancer- free for at least 5 years.⁵Data in the literature appear to indicate an increased risk of certain malignancies in patients with psoriasis, especially lymphohematopoietic, head and neck, and gastrointestinal tract cancers.

There is also an increased risk of non- melanoma skin cancers (NMSC), possibly as a result of prior therapies such as p-UVA phototherapy or cyclosporine. With regard to biologic drugs, some studies suggest a possible increased risk of NMSC in subjects treated with anti-TNF alpha, while there are no reports about the other molecules.⁶ However, there is a lack of long-term safety data regarding newer biologic agents, which leads to a very cautious use of them in patients with a history of cancer. This also tends to cause patients to be managed with topical therapies that are less effective in moderate-severe psoriasis, with a detriment of quality of life.

In this multifaceted scenario, DMF could represent a valid therapeutic choice in terms of safety. In our experience, in fact, DMF is an effective treatment option, generally well tolerated, with few side effects that recede by adjusting the dose or by dis- continuation of the drug.

Conclusions

This case is of interest because in patients with many comorbidities, there is a tendency to use only topical therapies or

phototherapy even in cases of moderate- severe psoriasis, with deterioration in the patient’s quality of life. Thus, DMF is a valid and safe therapeutic option in patients requiring systemic therapy either as a first line or in case of previous unsuccessful treatments.

References

1. Burlando M, Molle MF, Antonelli CT et al. Erythema multiforme after initiation of anti-interleukin-12/23 (ustekinumab) treatment for plaque psoriasis. JAAD Case Rep 2020;6:386-7.

2. Mrowietz U, Barker J, Boehncke WH et al. Clinical use of dimethyl fumarate in moderate-to-severe plaque-type psoriasis: a European expert consensus. J Eur Acad Dermatol Venereol 2018;32:3-14.

3. Blair HA. Dimethyl Fumarate: A Review in Moderate to Severe Plaque Psoriasis. Drugs 2018;78:123-30.

4. Mrowietz U, Szepietowski JC, Loewe R, et al. Efficacy and safety of LAS41008 (dimethyl fumarate) in adults with moderate-to-severe chronic plaque psoriasis: a randomized, double- blind, Fumaderm® - and placebo-controlled trial (BRIDGE). Br J Dermatol 2017;176:615-23. Erratum in: Br J Dermatol 2018;178:308.

5. Takeshita J, Grewal S, Langan SM, et al. Psoriasis and comorbid diseases:

Implications for management. J Am Acad Dermatol 2017;76:393-403.

6. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol 2019;80:1073-113.

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Dimethyl fumarate as a safe and effective therapy for recalcitrant psoriasis in comorbid patients

Martina Burlando, Mattia Fabio Molle, Emanuele Cozzani, Aurora Parodi Section of Dermatology, DISSAL, San Martino-IST Polyclinic Hospital, University of Genoa, Italy

Abstract

Psoriasis is a chronic condition for which multiple therapies are currently available. In particular, in cases of moderate-severe psoriasis, traditional systemic drugs or the new biological drugs can be administered. However, the treatment of patients who require systemic therapy and have multiple comorbidities can be particularly complex. Some treatment options may be in fact contraindicated or may lose effec- tiveness over time, reducing the options available to the dermatologists. In such cir- cumstances, dimethyl fumarate may represent a safe and effective choice, also in patients who have already attempted biological therapies. In this regard, we report the case of a patient with moderate-severe psoriasis treated over time with various therapies (including topicals, phototherapy, traditional and biological drugs) that were discontinued due to ineffectiveness or incompatibility caused by the occurrence of concomitant diseases, who finally achieved clinical remission with dimethyl fumarate.

Introduction

Psoriasis is a chronic, immune-mediat- ed, inflammatory disease characterized by the presence of indurated erythematous plaques covered by silvery desquamative scales that usually involve knees, elbows, trunk and scalp.¹Nowadays there are multiple therapeutic options available for the treatment of psoriasis, including topicals, phototherapy, traditional systemic and novel biologic agents.² Systemic therapies used in severe forms of disease are based on principles with immunosuppressive or immunomodulating activity, so it can be complex in patients with multiple underlying comorbidities to find the best therapy.

We present the case of a psoriatic patient with multiple pathologies and numerous previous treatments in which it was finally possible to obtain an excellent clinical con-

trol of the disease thanks to the use of dimethyl fumarate (DMF).

Case Report

A 57-year-old Caucasian man has been followed at our Dermatology Clinic since 2005 for plaque psoriasis with prevalent localization to the scalp, elbows, knees, inguinal and intergluteal folds. In his medical history, the patient presented chronic hepatitis C virus (HCV) infection.

Until 2012, the patient experienced good clinical control of the disease through the application of topical products (steroids and vitamin D analogues) together with bal- neophototherapy and periodic cycles of nb- UVB phototherapy.

In February 2013, the patient presented a marked clinical worsening characterized by numerous infiltrated erythematous- desquamative plaques on the trunk and limbs, with a Psoriasis Area Severity Index (PASI) score of 16. After hepatological consultation, a treatment with cyclosporine at the initial dose of 2.5 mg/kg/day was therefore started with immediate clinical response. However, after 4 months, therapy was discontinued because of an increase in serum creatinine and the patient returned to topical treatments. After several months of good clinical response, the patient had a new relapse in September 2014, with involvement of the scalp, trunk, limbs, and nail onycholysis of the hands and feet. The patient denied joint pain. At the same time, the patient tested positive to the QuantiFERON-TB Gold test and showed certain pulmonary nodules on chest X-ray.

A pneumological diagnostic work-up was carried out, including bronchoalveolar lavage and microscopic and cultural exami- nations, which excluded the presence of Mycobacterium tuberculosis strains or malignant tumor cells. Therefore, after hep- atologic consultation and the initiation of prophylactic therapy with isoniazid, the patient in February 2015 began a therapy with etanercept. At follow-up blood tests in May 2015, the patient unfortunately showed a significant increase in liver function indices so etanercept and isoniazid were discontinued, and the patient returned again to topical treatments. Meanwhile, in 2016, the patient began direct acting antiviral treatment for HCV with excellent response and normalization of liver function. Given the further worsening of psoriasis, etanercept in combination with topical treatments was started again in December 2016. On that occasion, the patient did not resume antituberculous prophylactic therapy due to

previous intolerance, and we opted for close follow-up visits. After an initial positive response, the patient experienced progres- sive secondary inefficacy so in June 2017 he was switched to adalimumab with immediate skin clearance. Unfortunately, the patient had at the same time a new progres- sive worsening of liver function and was listed for liver transplantation. In March 2018, following the finding of a liver nodule suggestive of malignancy, adalimumab therapy was discontinued. In April 2018, the patient underwent liver resection with a diagnosis of hepatocarcinoma. The psoriasis relapsed again; this time poorly respon- sive to topical treatments. Therefore, in September 2018, a therapy with apremilast was initiated, with modest results. Given the persistence of diffuse lesions after six months of therapy (PASI 10), a new cycle of

Dermatology Reports 2022; volume 14:9091

Correspondence: Martina Burlando, Section of Dermatology, DISSAL, San Martino-IST Polyclinic Hospital, University of Genoa, 16132 Genoa, Italy.

Tel.: +393491029766

E-mail: [email protected] Key words: Psoriasis, Dimethyl fumarate, Comorbidities, Biologics, Malignancy.

Contributions: Study conception and design:

MB, MFM, EC, AP. Acquisition of data: MB, MFM. Drafting of the manuscript: MFM.

Critical revision: MB, EC, AP.

Funding: None.

Ethics: All the procedures adopted in the present study were in respect to the ethical stan- dards in the World Medical Association Declaration of Helsinki. The subject gave his written informed consent to publish the present case (including publication of images).

Please cite this article as: Burlando M, Molle MF, Cozzani E, Parodi A. Dimethyl fumarate as a safe and effective therapy for recalcitrant psoriasis in comorbid patients. Dermatol Rep 2022;14:9091.

Received for publication: 30 January 2021.

Accepted for publication: 26 April 2021.

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tion. The antianginal drug was interrupted obtaining a rapid and surprising restitutio ad integrum which allow us to confirm the diagnosis of a KE-like reaction to ranolazine. Palmoplantar exfoliation can be a consequence of genetic defects, as happens in acral peeling skin syndrome, or can be triggered by infections, as tinea pedis and scarlet fever.³Less frequently it can be a localized manifestation of a cutaneous drug reaction,³ which may comprehend a variety of conditions that can affect acral vasomotility, hand pigmentation, skin and nails structure.² Many chemotherapeutic agents and molecular targeted therapies can cause hand-foot syndrome, or erythrodyses- thesia, which is an erythematous- desqua- mative and painful condition of palms and soles.⁴Cardiologic therapy can rarely cause palmo-plantar desquamation and literature provides evidence of few cases triggered by calcium channel blockers, especially diltiazem, amiodarone, enalapril and phenin- dione.⁵In our case we formulated the clinical diagnosis of KE, also known as dyshidrosis lamellosa sicca.⁶The condition is characterized by small, annular collarettes of white desquamation involving only the palms (and, less commonly, the soles) of hands and feet.⁶As in our case, mechanical friction and water contact may exacerbate the cleavage and partially degra- dation of corneodesmosomes within the stratum corneum, the absence of an inflammatory infiltrate is characteristic.⁶The dis- crete appearance of desquamation, limited to palms, the adult onset and the absence of inflammation signs allowed us to exclude both acral peeling skin and erythrodysesthe- sia. KE is a common but frequently under-

recognized peeling entity with has uncertain origin, have been described both sporadic and familial cases.⁶To our knowledge, literature offers evidence of only one other case of drug-induced KE, triggered by chloroquine intake.³We herein propose the first report of a KE-like eruption to ranolazine, an antianginal molecule which selectively inhibits the late sodium current.⁷Except the possibility of an immediate hypersensitivity reaction and urticaria onset, there are few evidence about ranolazine cutaneous side effects. Common side effects include dizzi- ness, nausea and constipation while peripheral oedema, headache, asthenia, palpita- tions, dyspepsia, weakness and postural hypotension are less frequently reported.⁸

Conclusions

Mild cutaneous drug reactions are insid- ious and challenging diagnoses because of the high risk of mimicking other dermatological patterns that can be more frequent and probable in specific anamnestic contexts. Patient those habits can be highly suggestive for occupational dermatitis can delay the correct diagnoses for months with serious impact to their job and their social life. In our opinion, dermatologists should always keep the focus on the possibility of a drug reaction also when clinical manifestations are limited to a part of the body, as happens in fixed erythema. We suggest per- forming a detailed and complete pharmaco- logical anamnesis during every medical examination as a good approach to patient in everyday clinical practice.

References

1. Sasseville D. Occupational contact dermatitis. Allergy Asthma Clin Immunol 2008;4:59-65.

2. Caccavale S, Ruocco E. Acral manifestations of systemic diseases: drug- induced and infectious diseases. Clin Dermatol 2017;35:55–63.

3. Nair PA, Patel T. Palmoplantar exfoliation due to chloroquine. Indian J Pharmacol 2017;49:205-7.

4. Nikolaou V, Syrigos K, Saif MW.

Incidence and implications of chemotherapy related hand-foot syndrome. Expert Opin Drug Saf 2016;15:1625-33.

5. Toescu SM, Kennon S, Stevens H.

Diltiazem-induced palmar desquamation and oral erosions. BMJ Case Rep 2013:bcr2013201536.

6. Chang YY, van der Velden J, van der Wier G, et al. Keratolysis exfoliativa (dyshidrosis lamellosa sicca): a distinct peeling entity. Br J Dermatol 2012;167:

1076-84.

7. Rayner-Hartley E, Sedlak T.

Ranolazine: a contemporary review. J Am Heart Assoc 2016;5:e003196.

8. Salazar CA, Basilio Flores JE, Veramendi Espinoza LE et al.

Ranolazine for stable angina pectoris.

Cochrane Database Syst Rev 2017;2:CD011747.

Figure 1. Exfoliative dermatitis of the palms characterized by

expanding collarettes of focal peeling of the stratum corneum. Figure 2. Complete restitutio ad integrumafter suspension of car- diologic therapy with ranolazine.

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Keratolysis exfoliativa-like eruption induced by ranolazine

Elena Pierobon,¹Lerica Germi,² Andrea Sechi,²Giampaolo Trevisan,² Elena Pezzolo,²Claudio Feliciani,¹ Luigi Naldi²

1Section of Dermatology, Department of Medicine and Surgery, University of Parma; ²Dermatology Unit, San Bortolo Hospital, Vicenza, Italy

Abstract

Dermatoses affecting palms may represent a dermatologic challenge from both the diagnostic, and therapeutic point of view.

Patients with supposedly occupational dermatitis can spend months or even years in a frustrating attempt to avoid contact with possible irritants or allergens. To underline the importance of a thorough unbiased analysis of the patient’s history and clinical features, we present the iconic case of a bricklayer affected by a chronic, disabling desquamation of palms which in the end was classified as keratolysis exfoliativa (KE) attributed to ranolazine-intake, an antianginal drug. To the best of our knowledge, this specific adverse effect of drug- induced KE of palms has never been reported before in association with ranolazine.

Case Report

We report the case of a 58 old man that was referred to our Dermatological Unit presenting a 2-years history of painful desquamation of both palms of the hands.

He had been working for over 20-years as a bricklayer and the skin condition was particularly disabling interfering with ordinary life and specific job tasks.

At the dermatological examination both hands appeared affected only on the palms, showing ill-defined collarettes of dry, peeled areas with tendency to painful fis- sures, resembling a keratolysis exfoliativa (KE) (Figure 1).

He had no evidence of other dermatological signs or symptoms and had no previous history or hereditary predisposition for cutaneous conditions, including psoriasis and atopic dermatitis. His medical history highlighted a cardiac ischemic disease for which he had for many years a chronic therapy with antihypertensive and cholesterol-lowering medicines to which had been added 2 years before a new

therapy with ranolazine to treat chronic stable angina pectoris.

Suspecting a chronic irritant contact dermatitis (ICD), we prescribed topical steroids to relieve the inflammation, sug- gested the use of protective gloves, barrier creams and moisturisers, providing also the appropriate information to prevent exposure to occupational irritants. The patient care- fully applied our indications but at the follow up visit his dermatitis seemed to have no improvement at all. We questioned the diagnosis of ICD and focused our attention to a possible delayed-type hypersensitivity reaction. At patch testing our patient was completely negative for the most frequent haptens for general population and building works (potassium dichromate, tiuram mix and nickel sulphate).

Far from ready to give up, we under- lined the temporal link from the first ranolazine intake and the onset of hand desquamation, both 2 years before. We suggest changing the cardiological therapy and after one month of ranolazine suspension, the patient’s skin recovered fully (Figure 2).

Discussion

Hand dermatoses are an extremely frequent cause of dermatological consultation and may be a consequence of lots of possible agents, exogenous or endogenous, sup- ported by irritative, allergic or infective agents. Frequently the clinical distribution and morphology of lesions are not enough specific to make the diagnosis because of a consistent risk of clinical mimicking of different aetiology. Collecting an accurate physiological anamnesis and medical history can be extremely important to investigate the role of constitutional predisposition and exogenous factors. The skin is the primary direct interface with external agents and patients those lesions affect the hands alone are likely to suffer from an occupational contact dermatitis¹. Considering daily contact of our patient with wet cement, clinical features, pain and burning sensation, our case was highly suggestive for an irritant chronic eczema (ICD). ICD is caused by chemical or physical skin damage and represent approximately 80% of all cases of occupational skin disorder.¹

At the failure of the first hypothesis, the second proposed diagnosis was equally possible: a minority of occupational dermatitis are allergic contact dermatitis (ACD) caused by a delayed-type hypersensitivity reaction.¹ Building workers can be commonly exposed to allergens which can be detected by a properly performed patch test-

ing. Not at least, lesions that are clinically suggestive for an infectious aetiology, mycotic or bacterial, can be easily ruled out thanks to microscopic and culture examination.²As these 3 most probable hypotheses came down, it is correct to focus the attention on the patient overall and reflect about the possibility of an endogenous mecha- nism, typical of atopic dermatitis. Although less frequent, in absence of anamnestic and clinical clues of constitutional eczema, dermatologists should consider the possibility of a drug reaction. In our case, underlying that ranolazine administration was started one month before the onset of disease, we suspected an acral drug-induced manifesta-

Dermatology Reports 2022; volume 14:9264

Correspondence: Elena Pierobon, Section of Dermatology, Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy.

Tel.: +39.0521.702711 - Fax: +39.0521.702959.

E-mail: [email protected] Key words: Keratolysis exfoliativa, Ranolazine, Cutaneous drug reaction, Hand dermatititis.

Contributions: EPi wrote most of the original draft of the paper. LG participated in drafting and designing the study. AS, EPe and GT had access to all the raw data of the study and participated in generating and gathering them.

LN and CF revised the work critically for important intellectual content and gave their contribute in the process of analysis and interpretation of data for the work. All authors participated in writing the paper and have approved the final version.

Funding: None.

Ethical approval and informed consent: ???

Please cite this article as: Pierobon E, Germi L, Sechi A, et al. Keratolysis exfoliativa-like eruption induced by ranolazine. Dermatol Rep 2022;14:9264.

Received for publication: 13 May 2021.

Accepted for publication: 12 July 2021.

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lenging both clinically and surgically. On one hand, we would like to underline the necessity to regard some uncommon diagnoses even if the observation doesn’t perfectly match all characteristics reported in literature. Extraneural PN is a rare entity that can be misdiagnosed because of unusu- al features that are not commonly reported because of the rarity of the diagnosis itself.

One the other hand, extraneural PN is a benign neoplasm with minimum risk of local recurrence and optimal prognosis after radical excision. Nevertheless, surgical removal of a tumor involving acral and functional sites could represent a challeng-

ing option even when considered the treatment of choice. The consequent reconstructive procedure could be even more important than the radical excision itself and should always be performed aiming at obtaining the best functional outcome for patient.

References

1. Uerschels AK, Krogias C, Junker A et al.

Modern treatment of perineuriomas: a case-series and systematic review. BMC Neurol 2020;20:1-12.

2. Rodríguez-Peralto JL, Riveiro- Falkenbach E, Carrillo R. Benign cutaneous neural tumors. Semin Diagn Pathol 2013;30:45-57.

3. Hornick JL, Fletcher CDM. Soft tissue perineurioma. Am J Surg Pathol 2005;59:845-58.

4. Carter JM, Wu Y, Blessing MM et al.

Recurrent genomic alterations in soft tissue perineuriomas. Am J Surg Pathol 2018;42:1708-14.

5. Yan H, Liu S, Gao W, et al. Management of degloving injuries of the foot with a defatted full-thickness skin graft. J Bone Joint Surg Am 2013;95:1675-81.

Figure 1. Clinical and dermatoscopic features of PN. A) A firm nodule of the sole of the foot of about 2 cm of diameter. B) Clinical detail of the well-circuscribed nodule with a homoge- neous pink-purple color. C) Dermatoscopic examination didn’t identify any specific vascular pattern and was featureless.

Figure 2. Surgical procedure and final outcome. A) Radical exci- sion of the nodule of the foot with safe margins. B) Integrity of the plantar fascia ligament, at the top of which the neoplasm was located without infiltrating it. C, D) Clinical outcome of the skin graft after 3 years, perfectly healed with full recovery of the mobil- ity function.

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Acral perineurioma: A case report of a rare neoplasm successfully treated with autologous skin graft reconstructive surgery

Elena Pierobon,¹Chiara Cortelazzi,² Michele Maria Dominici,¹Claudio Feliciani,¹Sergio Di Nuzzo¹

1Section of Dermatology, Department of Medicine and Surgery, University of Parma; ²Section of Dermatology, Department of Medicine and Surgery, University of Modena and Reggio Emilia, Modena, Italy

Abstract

Soft tissues perineurioma is a rare nerve sheath tumor that affects most of all the sub- cutaneous tissue. Even if it could present as a large mass, it is a benign neoplasm for which a complete surgical excision represents the gold standard treatment.

Considering that it usually affects acral sites of young people, it can be challenging to perform a reconstructive surgery that allows a full functional recovery. We report the case of a woman in her 20s presenting a perineurioma of the sole of the right foot, a nodule of about 2 cm of diameter that compromised the support of the foot on the ground. We performed a radical surgical excision with no recurrence after 3 years of follow up and we obtained a full functional recovery thanks to an autologous full-thickness skin graft.

Case Report

A woman in her 20s came to our attention presenting a nodular lesion of the right sole. She referred that the lesion slowly developed after a trivial trauma without any symptom. Her medical history was completely negative up to that moment and there was no evidence of familiar conditions such as neurofibromatosis. On clinical examination, we observed a single, rounded well circumscribed nodule, with a homoge- neous pink-purple color and hard on palpa- tion (Figure 1A,B). Dermatoscopic evalua- tion was nonspecific and featureless (Figure 1C).The mass was painless, but the patient complained an initial discomfort with the pressure of the foot on the ground due to the size of the neoplasm, that was about 2 cm of diameter.

Histopathological analysis of a first

incisional biopsy pointed to the diagnosis of perineurioma of soft tissues, even if the interpretation was more difficult because of the absence of the typical immunohistochemistry staining for the long cytoplasmic processes of perineurial cells (EMA).

We performed a complete surgical excision (Figure 2A), preserving the integrity of the plantar fascia ligament, that wasn’t infiltrated by the neoplasm (Figure 2B). The loss of substance of the wound was recon- structed harvesting and applying an autologous full-thickness skin graft that healed successfully (Figure 2C,D).

After radical excision, our patient perfectly recovered with no recurrence after 3 years of clinical follow up.

Discussion

PN is a rare nerve sheath tumor that originates exclusively from perineural cells, which take part in the blood-nerve barrier surrounding peripheral nerves.¹Depending on the relationship with the nerve enveloped, PNs are classified into intra- neural and extraneural ones, with different clinical presentation and etiology.²

As in our case, extraneural PN affects soft tissues and are mostly located in the subcutis.³Typically, it occurs on acral sites and trunk of young to middle-aged adults as asymptomatic masses which can slowly reach a remarkable size.³Extraneural PN is caused by deletions of chromosome 22q (with NF2 gene) or of chromosome 17q (with NF1 gene) so, as in other nerve sheath tumors, its onset can be facilitated in patients with neurofibromatosis.⁴

Nodules are usually yellow white, well circumscribed but unencapsulated.³Clinical appearance is so aspecific that the diagnosis is based only on histopathological and immunohistochemical criteria.³ Microscopically we observe low cellularity³ and atypical features in about 20% of sub- cutaneous perineuriomas, without a clinical significance.² Most of the tumor cells are positive for the epithelial membrane antigen (EMA) immunohistochemistry,³ that high- lights the cytoplasmic processes of perineurial cells.² EMA positivity is a useful diagnostic tool, but a small subset of tumors appears to lack it,³as in our observation.

A complete surgical excision is the treatment of choice even if the involvement of extremities and the onset among young people can make challenging to perform a radical approach and a consequent functional reconstructive surgery. Considering the weight-bearing function of the foot, a full thickness autologous skin graft is a good

treatment approach because not only it acts as wound coverage but also permits to achieve stability and durability of the recon- structed site, as in our case.⁵

Generally, the prognosis is good: only in few cases, about 5% in Hornick and Fletcher’s observations, a local recurrence is reported, while there is no evidence of metastasis.³

Conclusions

We report this case because it is chal-

Dermatology Reports 2022; volume 14:9093

Correspondence: Elena Pierobon, Section of Dermatology, Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy.

Tel.: +39.0521.702711 - Fax: +39.0521.702959.

E-mail: [email protected] Key words: Perineurioma, Full-thickness skin graft, Nerve sheath tumor, Acral neoplasm.

Contributions: EP participated collecting the data of the study and wrote the majority of the original draft of the paper. CC and MMD had access to all of the raw data of the study and participated in generating and gathering them.

CF revised the work critically for important intellectual content. SdN participated in drafting and designing the study and analysis and interpretation of data for the work. All authors participated in writing the paper and have approved the final version.

Funding: None.

Ethical approval and informed consent: ???.

Please cite this article as: Pierobon E, Cortelazzi C, Dominici MM, et al. Acral per- ineurioma: A case report of a rare neoplasm successfully treated with autologous skin graft reconstructive surgery. Dermatol Rep 2022;14:9093.

Received for publication: 13 May 2021.

Accepted for publication: 12 July 2021.

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the biological drug. Compliance with the treatment pathway, as defined by the guidelines, also brings benefits from the point of view of the economic impact on the National Health Service. In fact, the Budget Impact study analyzed how an increase in the use of Methotrexate could reduce the overall costs of patient management, generating savings in resources that the system could use to treat new patients.

In the treatment of patients with psoriasis there are important differences between Regions and even between individual Centres. An example of this is the management of waiting lists, which, being excessively long, force the patient to turn to different specialists in search of an adequate treatment, thus delaying the timing of treatment. This situation was worsened in 2020 by the recent Covid-19 pandemic, which led to further delays and greater difficulty in accessing treatment. In fact, public attention has focused on the issue of care guaranteed to non-Covid-19 patients, and it has emerged that, compared to 2019, outpatient specialist care has suffered a reduction of 18 million visits.

In addition, there is the experience of the outpatient setting, where the possibility of prescribing biological drugs depends on regional forecasts, causing a further diversification of patient management, both between regions and between local realities.

In conclusion, in order to standardize and promote proper care of patients with psoriasis, the Pso-Path Working Group agrees on the need to encourage the creation of a network that promotes collaboration and connection among all the actors involved in the overall care of the patient. In particular, it is deemed necessary that this network system be formalized in order to define the stages of the patient’s diagnostic-

therapeutic pathway and facilitate commu- nication and coordination channels between hospital and territory.

Of equal importance is the need to work on increasing awareness at the territorial level, in order to avoid situations in which the patient is referred to the specialist only at an advanced stage of the pathology, delaying, even for years, both a correct diagnosis and a prescription for appropriate treatment. This situation occurs, in fact, when symptoms are not correctly identified in the early stages of the disease and the patient’s progress is slowed down from the first contact. It is therefore good to insist on the importance and impact of the pathology and the possible pathways, in order to favour the possibility of recognising the symptoms at an early stage and to start the patient on an appropriate therapeutic pathway as defined by the guidelines. It is therefore desirable to formalize regional guidelines that define the points of contact within the pathway of the patient with psoriasis that take into account local specificities, set concrete goals in terms of increasing the appropriateness of care and offer shared criteria to reduce the variability of care of patients with psoriasis.

References

1. Prignano F, Rogai V, Cavallucci E, et al.

Epidemiology of Psoriasis and Psoriatic Arthritis in Italy-a Systematic Review.

Curr Rheumatol Rep 2018;20:43.

2. Zagni E, Colombo D, Fiocchi M, et al.

Pharmaco-utilization of biologic drugs in patients affected by psoriasis, psoriatic arthritis and ankylosing spondylitis in an Italian real-world setting. Expert Rev

Pharmacoecon Outcomes Res 2020;20:

491-7.

3. Multidisciplinary Working Group in Dermatology Emilia-Romagna Region.

Systemic treatment of moderate-severe chronic plaque psoriasis with particular reference to biotechnological drugs.

Therapeutic guideline no.1. Update May 2019 Assessorato Cura della per- sona, Salute e Welfare Regione Emilia- Romagna.

4. IQVIA Holdings Inc. IQVIA data 2nd quarter 2020. Available from:

https://s24.q4cdn.com/326377938/files/

doc_news/2020/07/22/IQVIA-Q2- 2020-Earnings-Press-Release_Final.pdf 5. Agenzia Italiana del Farmaco. National Observatory for medicines use.

National Report 2015. Rome: Agenzia Italiana del Farmaco, 2016.

6. Zagni E, Bianchi L, Fabbrocini G, et al.

A real-world economic analysis of biologic therapies for moderate-to-severe plaque psoriasis in Italy: results of the CANOVA observational longitudinal study. BMC Health Serv Res 2021;21:

7. Pompilio G, Integlia D, Aru C. Analisi924.

di impatto sul budget SSN di una mag- giore appropriatezza prescrittiva in prima linea del metotrexato nei pazienti con psoriasi di grado da moderato a severo. Available form: http://clini- coeconomics.eu/articles/flipbook/16_2 021_01-12/

8. Prignano F, Tripo L, Amato L, et al.

Tuscan consensus on the diagnosis, treatment and followup of moderate-to- severe psoriasis. G Ital Dermatol Venereol 2017;152:99-108.

9. 4th Salutequità Report. Missed cures in 2020. June 2021. Available from:

www.salutequita.it

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monies, a subsequent update of the text had been hypothesized after 2016, the hypothesis, however, was not followed up due to the difficulty of bringing together all the inde- fectible stakeholders and for the related economic effort. It is precisely the need to identify shared criteria for the appropriate use of biologic drugs that led Emilia- Romagna Region to draw up new Guidelines on the Treatment of Moderate- Severe Chronic Plaque Psoriasis. In May 2019, the multidisciplinary working group on Biotechnological Drugs in Dermatology of the Emilia- Romagna Region recommended the use of bDMARDs in case of non-response, intolerance or contraindication to Methotrexate and Cyclosporine.

Moreover, it states that Methotrexate is the reference drug, among first-line drugs, for the treatment of moderate-to-severe chronic plaque psoriasis.

Moreover, the need to define a clinical- therapeutic management process of the patient with psoriasis, which facilitates access to qualified services and appropriate care, while optimizing the use of healthcare resources, prompted Toscana Region to develop an ad hoc diagnostic-therapeutic protocol in 2014. This model of governance of the complexity of care and treatment aims to clarify the essential steps of patient management, from diagnosis to direct, continuous and planned follow-up.⁸

Observations of the Pso-Path Table It is first of all perceived that the num- ber of patients with psoriasis under treatment is considerably lower than what could be assumed considering the epidemiological data. This actually confirms the data available to date, according to which less than 10% of patients (37,500) receive systemic treatment with conventional DMARDs or biological drugs. The possible reasons identified are several. First of all, in the reflections of the Pso-Path Table, the lack of a precise system for taking charge of the patient that defines the stages of the diagnostic-therapeutic pathway, identifies the points of contact and enables all the actors involved to be aligned and coordinat- ed, has emerged with marked frequency. In the absence of such a definition, there is in fact the risk that the patient’s pathway will be hindered by the absence of appropriate links between the territory and the hospital, leaving to the specialists the attempt to cre- ate them on the basis of their own knowledge rather than of a structured taking charge system.

This pathway appears to be slowed down right from the first contact with the general practitioner, in which the ability to correctly identify the symptoms and direct

the patient, even in the early stages of the disease, towards the centre of reference is uncertain. All too often, in fact, the patient arrives at the specialist only at an advanced stage of the pathology, causing delays, even of years, both in the correct diagnosis and in the prescription of an appropriate treatment.

A further element brought to the attention of the members of the group concerns waiting lists, which are excessively long, pushing patients to turn to different specialists in search of adequate treatment. This continuous “search” and the relative move- ments can take months and, in this way, influence the timing of the treatment. This situation appears to be aggravated in the 2020s due to the recent Covid-19 pandemic, which has resulted in unprecedented difficulty in accessing treatment. In fact, missed treatment has become a real phenomenon that has focused public attention on the issue of care for non-Covid-19 patients. To take one example, according to a recent report, outpatient specialty care would have contracted from 2019 by 144.5 million fewer services, including more than 18 million visits.⁹

From the patients’ point of view, the need for an in-depth examination of the different levels of compliance with the Guidelines at the level of individual regions emerged. The perception of the variability of treatment, which can compromise an appropriate treatment of the patient and the possibility of having access to adequate care, deserves a reflection on possible discriminatory situations that may occur due to the diversification of approaches between regions. The patient, in fact, who needs to be taken care of by a dedicated and cus- tomised treatment system based on his clinical situation, takes the risk, in the absence of a well-defined treatment pathway, of being started on treatment with a biological drug without previous use of Methotrexate, effectively skipping a therapeutic option that constitutes an additional opportunity for treatment.

The perception of clinicians, according to their experience, confirms the data emerging from the National Report

“National Observatory on the Use of Medicines” (Osmed) compiled by AIFA in 2015, according to which more than 77% of patients with psoriasis are started on treatment with biological drugs without a previous use of Methotrexate or Cyclosporine for at least 3 months. These results were also confirmed by the real- world study conducted by CliCon, which showed that about 77% of patients with psoriasis undergoing treatment with biologic drugs had not received a therapy based on Methotrexate or Cyclosporine for a duration of at least 3

months in the year preceding biological treatment (the results were detailed in Section 2). Therefore, in actual clinical practice there is a deviation from the current guidelines recommending the use of biological drugs in case of non-response, intolerance or contraindication to Methotrexate or Cyclosporine. In addition to this, there is the experience of the outpatient setting where the possibility of prescribing biological drugs depends on regional forecasts, causing a further diversification of patient management, both between regions and between local realities.

From the point of view of the economic impact on the NHS, a recent Budget Impact study showed how a 50% increase in the use of Methotrexate can reduce the overall costs of patient management, generating a saving of € 35.5 million over a two-year period and considering a potential population of 45,560 patients. In these terms, the working group stressed the importance of prescribing first- line drugs identified by the Guidelines, including Methotrexate, since in the event of a patient not responding to treatment with a biologic, skipping therapy with Methotrexate corresponds to corresponds to a complete obliteration of a therapeutic opportunity with both clinical and economic consequences.

Conclusions

Currently it is estimated that in Italy there are about 1.8 million patients with psoriasis, of which about 500,000 with moderate-severe forms. Available data show that only 37,500 patients are under systemic treatment with conventional DMARDs or Biological drugs.

Based on its experience as clinicians, economists and patients, the Pso-Path Working Group first of all believes that compared to epidemiological data, the num- ber of patients with psoriasis treated is small and further confirms that many patients diagnosed with psoriasis do not follow the treatment path outlined by the Guidelines with prior use of Methotrexate.

During the discussion, it was pointed out that there is a marked variability in the management of the disease and the need to identify shared criteria to ensure appropriate patient care in order to avoid possible discriminatory situations that may occur due to the diversification of approaches between regions. Moreover, compliance with the treatment pathway, as defined by the guidelines, is considered essential for the patient to benefit from Methotrexate as a therapeutic opportunity prior to the use of

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response or intolerance (therapeutic failure) to a conventional synthetic DMARD.

Studies show that about 25-30% of patients have moderate-severe forms of psoriasis¹. It follows that in Italy about 500,000 patients are affected. A recent retrospective study on the administrative databases of two Italian regions showed that out of 211,561 patients with psoriasis, 1.1%

underwent therapy with biological drugs.²A data analysis on treatments used by patients with moderate-severe psoriasis shows that only 37,500 (7%) are on systemic treatment with conventional DMARDs or biologic drugs.⁴At a first reflection, it is immediate- ly evident that, compared to the assumed epidemiology, the patients treated with systemic drugs, as required by the guidelines, are quite small.

In addition, despite the indications, the treatment path of psoriasis is not in line with the guidelines.

Data emerged in 2015 from the National Report “National Observatory on the Use of Medicines” (Osmed) prepared by AIFA. In fact, it is noted that in that year the percentage of patients with psoriasis who have started treatment with biological drugs without previous use of Methotrexate or Cyclosporine for at least 3 months was 77%.⁵

The costs analysis, subject of a recent multicentre observational study,⁶ also deserves some reflection. In order to verify how better prescribing of Methotrexate, as expected by the Guidelines, can have an economic impact on the National Health Service, a Budget Impact study was recently conducted, showing that increasing the use of Methotrexate by 50% (from 22.05%

to 33.08%) can reduce the overall costs of patient management. Specifically, the study showed the ability to generate national savings of 35.5 million Euros over a two-year time horizon and considering a potential population of 45,560 patients.⁷

The aim of this paper is to provide insights into the psoriasis patient pathway and to collect observations, criticalities and proposals for improvement from the Pso- Path Working Group, of health economists, clinicians and patients. To this end, the currently available epidemiological data will be taken into consideration, reflecting on the need for their revision and then analysing the causes of the deviation of clinical practice from the current guidelines for the management of patients with psoriasis, finally proposing initiatives for improvement to avoid inappropriate prescription.

Materials and methods

The Pso-Path Table

This document is the result of a multi- professional discussion that has as its object the analysis of the deviation of clinical practice from the current guidelines on the care of patients with psoriasis. For this purpose, a working group, called Pso-Path, was created, composed of health economists (CliCon S.r.L.) and representatives of the Confederation of Regional District Associations (CARD), of the Association of Italian Hospital Dermatologists- Venereologists and Public Health (ADOI), of the International-Italian Society of Plastic- Regenerative and Oncologic Dermatology (ISPLAD), of the Italian Association of Ambulatory Dermatologists (AIDA), of the Italian Psoriatic Association Friends of the Corazza Foundation (APIAF- CO).The Pso-Path working group, involving scientific societies and patients on the topic of psoriasis, was motivated by the common goal of identifying areas of improvement in the current diagnostic and therapeutic setting of people with psoriasis and proposing, first of all to regional institutions, models of care and therapeutic approaches that are more effective and in line with clinical guidelines.

The Working Group discussed the results of a recent study “Analisi del percor- so terapeutico nei pazienti affetti da psoriasi avviati al trattamento con farmaci biologi- ci” carried out by CliCon, whose purpose was to analyze the patterns of conventional systemic treatments prior to biological therapy in patients with psoriasis started with biological drugs, in Italian contexts of clinical practice using real-world data. The discussion of the experts also focused on the examination of the Guidelines currently available, bringing the personal contribu- tion derived from their experience of clinical practice.

Results

Analysis of clinical practice and guidelines

The reflections of the Pso-Path have taken into consideration first of all the epidemiological data currently available.

According to these, in fact, it is estimated that in Italy there are about 1.8 million patients with psoriasis, of which about 500,000 with moderate-severe forms. We

then tried to understand how these patients were treated. The data available today indicate that only 37,500 patients receive systemic treatment with conventional DMARDs or biologic drugs. Hence the need to understand what mechanisms influence the non-compliance with the Guidelines in the current diagnostic and therapeutic setting of people with psoriasis.

In addition, a temporal analysis was performed in order to measure the time interval between the use of the first-line drug and the biologic, thus investigating whether the patient’s pathway to treatment with biologic is attributable to the failure of the first-line treatment or to other factors.

Recently, CliCon has carried out a retrospective observational study on the services provided and in charge of the NHS for patients diagnosed with psoriasis and started on biological therapy, between January 2013 and October 2019 (inclusion period), analysing a sample of about 3.5 million assisted (details of the methodology are reported in Section 1). The results of this analysis showed a suboptimal prescriptive appropriateness for psoriasis found in real clinical practice: in fact, of the 495 patients included with psoriasis and being treated with biological drugs, only 43.2% (N=214) had been treated with Methotrexate or Cyclosporine in the year before the start of biological therapy, and of these 52.3%

(N=112) had received conventional treatment for a period of at least 3 months.

Considering the entire population included (N=495), only 22.6% of patients had received Methotrexate or Cyclosporine therapy for at least 3 months in the year prior to biological treatment.

It was also found that if the whole period before the index date is considered, this percentage is reduced to 18.6 (Section 2).

Data emerged from the study were the starting point for the reflections of the working group on the actual compliance of clinical practice with the guidelines. During the discussion it emerged in fact that, according to the experience of clinicians, there is a marked variability in the management of the disease and that many patients referred directly to the treatment with biological drugs, do not follow the treatment path outlined. According to the current Guidelines of the Istituto Superiore di Sanità issued in 2013, and updated in 2016, it is recommended the use of Methotrexate - as well as Cyclosporine and Acitretin - for the treatment of severe or plaque psoriasis while the recourse to the use of biological drugs should occur for patients with severe psoriasis who do not respond or have contraindications or are intolerant to systemic therapies. According to experts’ testi-

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Methotrexate in the therapeu- tic pathway of patients with psoriasis. Analysis of clinical practice data and comparison with guidelines

Valeria Corazza,¹Francesco Cusano,² Ornella De Pità,³Luigi Rossi,⁴ G. Giovanni Virno⁵

1President of the Italian Psoriatic Association Friends of the Corazza Foundation (APIAFCO); ²President of the Association of Italian Hospital Dermatologists Venereologists and Public Health (ADOI); ³President of the International - Italian Society of Plastic- Regenerative and Oncologic

Dermatology (ISPLAD); ⁴President of the Confederation of Regional District Associations of Tuscany Region (CARD); ⁵Member of the Board of Directors Italian Association of Ambulatory Dermatologists (AIDA), Italy

Abstract

Psoriasis is an inflammatory skin disease with a chronic-relapsing course. It is estimated that the prevalence in Italy is 3%.

An adequate model of taking care of the patient with psoriasis allows the patient to benefit from the most suitable treatment option for his health needs. In this position statement the observations, criticalities and proposals for improvement of the Pso-Path Working Group, composed by health economists, clinicians and patients, on the diagnostic-therapeutic pathway of the patient with psoriasis have been collected.

In particular, the deviation of clinical practice from the current Guidelines for the management of patients with psoriasis, which recommend the use of biologic drugs in case of non-response, intolerance or contraindication to Methotrexate or Cyclosporine, was evaluated. A Working Group was convened whose participants were asked to express their thoughts on the diagnostic and therapeutic pathway of the patient with psoriasis, bringing out critical elements and proposals for improvement, based on their experiences. This position statement summarizes the experiences and consensus between clinicians and patients on actions to optimize the management of patients with psoriasis undergoing biological treatment. Compared to the epidemiological data currently available, it is

believed that only a small percentage of patients with psoriasis are treated with systemic drugs. The perception of clinicians, according to their experience, confirms the data emerging from the National Report

“National Observatory on the Use of Medicines” (Osmed) compiled by AIFA in 2015, according to which more than 77% of patients with psoriasis are started to treatment with biological drugs without a previous use of Methotrexate or Cyclosporine for at least 3 months. The Pso-Path Working Group concluded that it would be desirable to incentivize, through the formalization of regional guidelines, the creation of a network system that promotes not only a greater awareness, at the territorial level, of the importance and impact of the disease and the possible paths, but also the collaboration and connection between all the actors involved in the overall care of the patient.

Introduction

Psoriasis is a chronic-recurrent inflammatory skin disease that commonly mani- fests itself with lesions or plaques characterized by erythema and/or desquamation. In Italy, it is estimated that about 1,800,000 people are affected by psoriasis as the prevalence in the population is 3%.¹ In a recent retrospective study on the administrative databases of two Italian regions, which included 8 million patients, 211,561 patients with psoriasis were identified, rep- resenting 2.6%.² Moderate-severe forms affect about ¼ of patients.

The disease, because of its specifically cutaneous manifestation, which is often very visible, also has a significant impact on the quality of life of patients causing diffi- culties in interpersonal, social and work relationships, even reducing their self- esteem. Knees, palms of the hands, elbows, soles of the feet, scalp, genitals, trunk, are just some of the areas generally affected.

For the treatment of moderate-severe psoriasis, the use of systemic drugs is expected and, in case of ineffectiveness or intolerance, the use of biologics. However, in clinical practice the management of the pathology is rather variable.

The European guidelines

“EuroGuiDerm Guideline on the systemic treatment of Psoriasis vulgaris - Part 1:

treatment and monitoring recommendations - Nast et al. “, published in 2020, recommend the initiation of conventional systemic treatments as a first line of treatment, taking into account national reimbursement conditions.

In Italy, the current Guidelines of the

Istituto Superiore di Sanità issued in 2013 and updated in 2016 recommend: i) the use of Methotrexate - as well as Cyclosporine and Acitretin - for the treatment of severe or plaque psoriasis; ii) the use of biologic drugs in patients with severe psoriasis who do not respond or have contraindications or are intolerant to systemic therapies.

In May 2019, in order to identify shared criteria for the appropriate use of biologic drugs, the multidisciplinary working group on Biotechnological Drugs in Dermatology of the Region of Emilia-Romagna has drawn up new Guidelines on the Treatment of Chronic Moderate-Severe Plaque Psoriasis recommending the use of bDMARDs in case of non-response, intolerance or contraindication to Methotrexate and Cyclosporine. Furthermore, it states that Methotrexate is the reference drug, among first-line drugs, for the therapy of chronic moderate-to-severe plaque psoriasis.³

Is to be considered also the AIFA Determination No. 699 of April 15, 2019 published in G.U. No. 93 of April 19, 2019 in which it is provided that the treatment with biological drugs in NHS charge should be limited to patients with plaque psoriasis, moderate to severe grade, in case of non-

Dermatology Reports 2022; volume 14:9454

Correspondence: Ornella De Pità, President of the International-Italian Society of Plastic- Regenerative and Oncologic Dermatology (ISPLAD), Italy.

E-mail: [email protected]

Key words: Psoriasis; Methotrexate; Posistion paper; Pso-Path Working Group.

Contributions: The authors contributed equally.

Funding: None.

Please cite this article as: Coraza V, Cusano F, De Pità O, et al. Methotrexate in the thera- peutic pathway of patients with psoriasis.

Analysis of clinical practice data and compar- ison with guidelines. Dermatol Rep 2022;14:9454.